TGF-β-responsive CAR-T cells promote anti-tumor immune function.

A chimeric antigen receptor (CAR) that responds to transforming growth factor beta (TGF-β) enables the engineering of T cells that convert this immunosuppressive cytokine into a potent T-cell stimulant. However, clinical translation of TGF-β CAR-T cells for cancer therapy requires the ability to productively combine TGF-β responsiveness with tumor-targeting specificity. Furthermore, the potential concern that contaminating, TGF-β?producing regulatory T (Treg) cells may preferentially expand during TGF-β CAR-T cell manufacturing and suppress effector T (Teff) cells demands careful evaluation. Here, we demonstrate that TGF-β CAR-T cells significantly improve the anti-tumor efficacy of neighboring cytotoxic T cells. Furthermore, the introduction of TGF-β CARs into mixed T-cell populations does not result in the preferential expansion of Treg cells, nor do TGF-β CAR-Treg cells cause CAR-mediated suppression of Teff cells. These results support the utility of incorporating TGF-β CARs in the development of adoptive T-cell therapy for cancer

Promoter Attenuation in Gene Therapy: Interferon-γ and Tumor Necrosis Factor-α Inhibit Transgene Expression

Overview summary Transgene expression can be eliminated even in the presence of substantial amounts of vector DNA in the transduced cells, which suggests that mechanisms other than the antigen-specific immune response may mediate non-cytodestructive events that determine the presence of transgene expression. Our data indicate that the cytokines interferon-γ) (IFN-γ) and tumor necrosis factor-α (TNF-α) inhibit transgene expression from certain widely used viral promoters/enhancers (human cytomegalovirus immediate early, Rous sarcoma virus long terminal repeat, simian virus 40, Moloney murine leukemia virus long terminal repeat) delivered by adenoviral, retroviral, or plasmid vectors in vivo. Inhibition is at the mRNA level and cytokines do not cause vector DNA degradation, inhibit total cellular protein synthesis, or kill infected/transfected cells. Thus, cytokine-regulated promoter function rather than specific immune destruction could limit transgene expression. These results have significant implications for the construction of transfer vectors for human gene therapy because gene transfer vectors could be exposed to a cytokine-rich environment when they are administered in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63157/1/hum.1997.8.17-2019.pd

Risk Assessment of Musculoskeletal Disorders Using Artificial Intelligence

Agricultural ergonomics employs methods such as Rapid Upper Limb Assessment (RULA) and Rapid Entire Body Assessment (REBA) to assess postural risks. However, these methods may be inaccurate and time-consuming. The objective of this study is to compare the effectiveness of Artificial Intelligence (AI), specifically a software based on MediaPipe, with conventional methods (RULA-REBA) to identify and assess ergonomic risks due to postures in rice agriculture. The methodology employed involved the development of AI software with MediaPipe, which was designed to detect postures in real time. This model was capable of identifying 33 anatomical points, thereby enabling detailed analysis of movement and posture. The results demonstrated that the AI outperformed RULA and REBA in detecting forced postures. Furthermore, it provided faster and more accurate assessments. The findings indicated that AI could be a valuable tool in agricultural ergonomics, potentially outperforming traditional methods. This could significantly improve working conditions and reduce musculoskeletal disorders among farmers

Aporte de la normativa especial de predios existentes residuales de densificación a la consolidación del tejido urbano

La densificación urbana es consecuencia de la necesidad de organizar el crecimiento y optimizar el uso de los recursos, promueve la democratización en el acceso a los bienes y servicios que ofrecen las centralidades y las mejores dotaciones. La instalación de las políticas densificatorias ocurren gradualmente, generando transformaciones que afectan a la morfología de la ciudad y provocan cambios generalmente rechazados por los habitantes originales, que los perciben como una agresión que afecta el hábitat que intentan conservar, circunstancia que suele incrementarse debido a la percepción de pérdida de privacidad que produce la edificación en altura y el aumento poblacional intensificado por el uso del equipamiento. Esta situación evidencia que las decisiones destinadas a fortalecer las estructuras urbanas deben observar las singularidades, porque independiente de que ser originario de una determinada zona no condiciona exclusividad en el beneficio de los atributos que ofrece, la habitualidad en el acceso a ellos se percibe como un derecho al que difícilmente se está dispuesto a renunciar, por lo que las decisiones de densificación deben no solo intentar resolver la inequidad en la disponibilidad de atributos urbanos sino que necesariamente deben incluir oportunidades para los que sostuvieron y contribuyeron a instalar los territorios.Área temática 4: Ciudad, Territorio y Paisaje. Gestión - Eje InvestigaciónFacultad de Arquitectura y Urbanism

Aporte de la normativa especial de predios existentes residuales de densificación a la consolidación del tejido urbano

La densificación urbana es consecuencia de la necesidad de organizar el crecimiento y optimizar el uso de los recursos, promueve la democratización en el acceso a los bienes y servicios que ofrecen las centralidades y las mejores dotaciones. La instalación de las políticas densificatorias ocurren gradualmente, generando transformaciones que afectan a la morfología de la ciudad y provocan cambios generalmente rechazados por los habitantes originales, que los perciben como una agresión que afecta el hábitat que intentan conservar, circunstancia que suele incrementarse debido a la percepción de pérdida de privacidad que produce la edificación en altura y el aumento poblacional intensificado por el uso del equipamiento. Esta situación evidencia que las decisiones destinadas a fortalecer las estructuras urbanas deben observar las singularidades, porque independiente de que ser originario de una determinada zona no condiciona exclusividad en el beneficio de los atributos que ofrece, la habitualidad en el acceso a ellos se percibe como un derecho al que difícilmente se está dispuesto a renunciar, por lo que las decisiones de densificación deben no solo intentar resolver la inequidad en la disponibilidad de atributos urbanos sino que necesariamente deben incluir oportunidades para los que sostuvieron y contribuyeron a instalar los territorios.Área temática 4: Ciudad, Territorio y Paisaje. Gestión - Eje InvestigaciónFacultad de Arquitectura y Urbanism

Aporte de la normativa especial de predios existentes residuales de densificación a la consolidación del tejido urbano

La densificación urbana es consecuencia de la necesidad de organizar el crecimiento y optimizar el uso de los recursos, promueve la democratización en el acceso a los bienes y servicios que ofrecen las centralidades y las mejores dotaciones. La instalación de las políticas densificatorias ocurren gradualmente, generando transformaciones que afectan a la morfología de la ciudad y provocan cambios generalmente rechazados por los habitantes originales, que los perciben como una agresión que afecta el hábitat que intentan conservar, circunstancia que suele incrementarse debido a la percepción de pérdida de privacidad que produce la edificación en altura y el aumento poblacional intensificado por el uso del equipamiento. Esta situación evidencia que las decisiones destinadas a fortalecer las estructuras urbanas deben observar las singularidades, porque independiente de que ser originario de una determinada zona no condiciona exclusividad en el beneficio de los atributos que ofrece, la habitualidad en el acceso a ellos se percibe como un derecho al que difícilmente se está dispuesto a renunciar, por lo que las decisiones de densificación deben no solo intentar resolver la inequidad en la disponibilidad de atributos urbanos sino que necesariamente deben incluir oportunidades para los que sostuvieron y contribuyeron a instalar los territorios.Área temática 4: Ciudad, Territorio y Paisaje. Gestión - Eje InvestigaciónFacultad de Arquitectura y Urbanism

Oportunidad para el desarrollo de terrenos islas en la comuna de Las Condes

This paper analyzes the effects and potential of a regulation intended to mitigate the consequences of a densification process that took place from 2003 within the context of a regulatory plan promoted by the municipality of Las Condes. Such an initiative intends to enable development opportunities for properties smaller than the minimum required and that have no opportunity for merging as the result of the densification of the surrounding environment. According to a survey conducted by this research, the analysis of different developments implemented within the context of this initiative and the identification of lands that may benefit from this provision enabling the categorization of management opportunities and measures intended to promote different development opportunities which, by carefully respecting particularities, incorporate participation as a tool for control and to ensure balance within the context of urban densification.Se analiza el efecto y potencialidad de la normativa de predio residual destinada a mitigar las consecuencias de la densificación instalada en el año 2003 en el plan regulador de la comuna de Las Condes que, en lo fundamental, está destinada a posibilitar el desarrollo de oportunidades para los predios que presentan superficie inferior a la mínima exigida y que no tienen opción de fusión, porque los entornos inmediatos han sido densificados. El catastro y evaluación de los desarrollos acogidos a la normativa y la detección de predios que podrían asumirla permitió formular una clasificación de oportunidades de gestión y de medidas destinadas a promover la diversidad de opciones de desarrollo que, respetando las individualidades, incorporan la participación como instancia de control y aseguramiento del equilibrio en la densificación urbana

Shorter Disease Duration Is Associated With Higher Rates of Response to Vedolizumab in Patients With Crohn's Disease But Not Ulcerative Colitis.

Background & aimsPatients with Crohn's disease (CD), but not ulcerative colitis (UC), of shorter duration have higher rates of response to tumor necrosis factor (TNF) antagonists than patients with longer disease duration. Little is known about the association between disease duration and response to other biologic agents. We aimed to evaluate response of patients with CD or UC to vedolizumab, stratified by disease duration.MethodsWe analyzed data from a retrospective, multicenter, consortium of patients with CD (n = 650) or UC (n = 437) treated with vedolizumab from May 2014 through December 2016. Using time to event analyses, we compared rates of clinical remission, corticosteroid-free remission (CSFR), and endoscopic remission between patients with early-stage (≤2 years duration) and later-stage (>2 years) CD or UC. We used Cox proportional hazards models to identify factors associated with outcomes.ResultsWithin 6 months initiation of treatment with vedolizumab, significantly higher proportions of patients with early-stage CD, vs later-stage CD, achieved clinical remission (38% vs 23%), CSFR (43% vs 14%), and endoscopic remission (29% vs 13%) (P < .05 for all comparisons). After adjusting for disease-related factors including previous exposure to TNF antagonists, patients with early-stage CD were significantly more likely than patients with later-stage CD to achieve clinical remission (adjusted hazard ratio [aHR], 1.59; 95% CI, 1.02-2.49), CSFR (aHR, 3.39; 95% CI, 1.66-6.92), and endoscopic remission (aHR, 1.90; 95% CI, 1.06-3.39). In contrast, disease duration was not a significant predictor of response among patients with UC.ConclusionsPatients with CD for 2 years or less are significantly more likely to achieve a complete response, CSFR, or endoscopic response to vedolizumab than patients with longer disease duration. Disease duration does not associate with response vedolizumab in patients with UC

PatientExploreR: an extensible application for dynamic visualization of patient clinical history from electronic health records in the OMOP common data model.

MotivationElectronic health records (EHRs) are quickly becoming omnipresent in healthcare, but interoperability issues and technical demands limit their use for biomedical and clinical research. Interactive and flexible software that interfaces directly with EHR data structured around a common data model (CDM) could accelerate more EHR-based research by making the data more accessible to researchers who lack computational expertise and/or domain knowledge.ResultsWe present PatientExploreR, an extensible application built on the R/Shiny framework that interfaces with a relational database of EHR data in the Observational Medical Outcomes Partnership CDM format. PatientExploreR produces patient-level interactive and dynamic reports and facilitates visualization of clinical data without any programming required. It allows researchers to easily construct and export patient cohorts from the EHR for analysis with other software. This application could enable easier exploration of patient-level data for physicians and researchers. PatientExploreR can incorporate EHR data from any institution that employs the CDM for users with approved access. The software code is free and open source under the MIT license, enabling institutions to install and users to expand and modify the application for their own purposes.Availability and implementationPatientExploreR can be freely obtained from GitHub: https://github.com/BenGlicksberg/PatientExploreR. We provide instructions for how researchers with approved access to their institutional EHR can use this package. We also release an open sandbox server of synthesized patient data for users without EHR access to explore: http://patientexplorer.ucsf.edu.Supplementary informationSupplementary data are available at Bioinformatics online

Grey-matter texture abnormalities and reduced hippocampal volume are distinguishing features of schizophrenia

Neurodevelopmental processes are widely believed to underlie schizophrenia. Analysis of brain texture from conventional magnetic resonance imaging (MRI) can detect disturbance in brain cytoarchitecture. We tested the hypothesis that patients with schizophrenia manifest quantitative differences in brain texture that, alongside discrete volumetric changes, may serve as an endophenotypic biomarker. Texture analysis (TA) of grey matter distribution and voxel-based morphometry (VBM) of regional brain volumes were applied to MRI scans of 27 patients with schizophrenia and 24 controls. Texture parameters (uniformity and entropy) were also used as covariates in VBM analyses to test for correspondence with regional brain volume. Linear discriminant analysis tested if texture and volumetric data predicted diagnostic group membership (schizophrenia or control). We found that uniformity and entropy of grey matter differed significantly between individuals with schizophrenia and controls at the fine spatial scale (filter width below 2 mm). Within the schizophrenia group, these texture parameters correlated with volumes of the left hippocampus, right amygdala and cerebellum. The best predictor of diagnostic group membership was the combination of fine texture heterogeneity and left hippocampal size. This study highlights the presence of distributed grey-matter abnormalities in schizophrenia, and their relation to focal structural abnormality of the hippocampus. The conjunction of these features has potential as a neuroimaging endophenotype of schizophrenia